Practically, pamoic acid salts of active pharmaceutical ingredients (APIs) have received very little attention either by pharmaceutical scientists or synthetic organic chemists. Two simplistic observations are recurring themes in the folklore (i.e. industry practice or belief) surrounding pamoic acid derivatives. In general, the preparation of a pamoate salt converts a liquid material to a solid and an improved organoleptic property has been ascribed to such salts. Organoleptic properties, for example, are smell and taste, and pamoate salts of drug substances have been suggested as eliminating the bitter taste compared with other salts (or the free base) of the drug substance. Rationally and chemically, these attributes can be assigned to pamoate salts.
It is of some historical interest that the pamoate salts of a variety of active pharmaceutical ingredients have received attention, noting that an embonate salt is identical to a pamoate salt. In the following cited literature, the pamoate was apparently chosen a) for converting a liquid active pharmaceutical ingredient into a solid, b) for eliminating the bitter taste associated with many active pharmaceutical ingredients, or c) as a process for isolating and then chemically characterizing otherwise difficult to delineate alkaloids or active pharmaceutical ingredients. For instance, U.S. Pat. No. 5,232,919 [Scheffler, et al.], the disclosure of which is totally incorporated herein by reference, discloses azelastine embonate and pharmaceutical formulations/compositions which contain it; said embonate salt to eliminate the bitter taste of azelastine alone.
Further, the French Patent 1,461,407 [Saias, et al.], the disclosure of which is totally incorporated herein by reference, discloses a process for the preparation of amine pamoates where the amine component includes piperazine, promethazine, papaverine, pholocodine, codeine, narcotine and chlorpheniramine.
The United Kingdom Patent Specification 295,656, [Carpmaels & Ransford, agents for applicants] the disclosure of which is totally incorporated herein by reference, discloses a process for the manufacture of poorly soluble salts of organic bases and alkaloids. The disclosure further indicates the process for manufacture provides sparingly soluble and tasteless salts of organic nitrogenous basic compounds including alkaloids.
U.S. Pat. No. 3,502,661 [Kasubick, et al.], the disclosure of which is totally incorporated herein by reference, discloses a process for the preparation of variously substituted pyridinium and imidazolines along with their acid addition salts. Some examples indicate pamoate salts prepared for select organic bases.
U.S. Pat. No. 2,925,417 [Elslager, et al.], the disclosure of which is totally incorporated herein by reference, discloses quinolinium salts of pamoic acid and a process for their manufacture.
Further, the following cited references indicate the incorporation of pamoate salts in pharmaceutical formulations for providing the controlled release of water insoluble polypeptides or the oil soluble azelastine. Hence, U.S. Pat. No. 5,776,885 [Orsolini, et al], the disclosure of which is totally incorporated herein by reference, discloses a pharmaceutical composition for the sustained and controlled release of water insoluble polypeptides whereby the therapeutically active peptide is in the form of its pamoate, tannate or stearate salt.
U.S. Pat. No. 5,445,832 [Orsolini, et al.], the disclosure of which is totally incorporated herein by reference, discloses a process for the preparation of microspheres made of a biodegradable polymeric material whereby a water soluble peptide or peptide salt is converted into a corresponding water-insoluble peptide salt selected from pamoates, stearates or palmitates of the peptide.
U.S. Pat. No. 5,439,688 [Orsolini, et al.], the disclosure of which is totally incorporated herein by reference, discloses a process for preparing a pharmaceutical composition in the form of microparticles designed for the controlled release of a drug that includes a biodegradable polymer and where the active ingredient can be selected from a group of possible salts, one being a pamoate.
U.S. Pat. No. 5,271,946 [Hettche] the disclosure of which is totally incorporated herein by reference, discloses a controlled release azelastine containing pharmaceutical composition whereby azelastine is incorporated into the formulation as its pamoate or other pharmaceutically active salt.
U.S. Pat. No. 5,225,205 [Orsolini, et al.], the disclosure of which is totally incorporated herein by reference, discloses a pharmaceutical composition in the form of microparticles; the formulation consisting of a peptide as its pamoate, tannate, stearate or palmitate salt; the formulation to provide a controlled release, pharmaceutical composition for the prolonged release of a medicamentous substance.
While the patent literature describes a number of known active pharmaceutical ingredients as their pamoate salts, surprisingly the Food and Drug Administration (FDA) has only three commercial products currently approved containing the pamoate moiety. These products are hydroxyzine pamoate, imipramine pamoate and triptorelin pamoate. Clearly, the pamoate moiety is an under-represented class of pharmaceutical salts and there remains a need to further explore the benefits available from producing pamoate salts of APIs.
In their Guidance for Industry, ANDAs: Pharmaceutical Solid Polymorphism, the United States Food and Drug Administration (FDA) has focused attention on the importance of characterizing the polymorphic behavior of an Active Pharmaceutical Ingredient (API) and the impact that behavior has on the commercial presentation of a formulated drug product. Indeed, the physical and chemical properties of an API's different polymorphs often display different behavior in their intended application and are known to influence and/or impact properties important to pharmaceutical compositions. These properties include the API's bioavailability, solubility, dissolution behavior, stability profile, permeability and manufacturing handling robustness including but not limited to uniformity of mixing, compaction in compression steps for tablet making, and the flow characteristics of the bulk blend.
The pharmaceutical industry has responded to the cited FDA Guidance and a number of patents have been allowed that provide solutions to a host of problems arising from polymorphic issues. In some cases, a given issue or problem was resolved by formulating a drug product with a specific API polymorph. In other cases, a new API polymorph was isolated and characterized to overcome prior art and/or to solve a technical issue. A few examples are representative of the substantive activity in polymorph research and development for pharmaceutical compositions.
A method for obtaining the most thermodynamically stable polymorph of formoterol tartrate and its subsequent purification by recrystallization is described in U.S. Pat. No. 6,472,563 (Tanoury, et al.), incorporated herein by reference. Tanoury et al. in U.S. Pat. No. 6,720,453, the disclosure of which is totally incorporated herein by reference, also in relation to formeterol tartrate polymorphs, describe a process for obtaining a highly pure salt of a single enantiomer of the API.
An instructive series of patents include U.S. Pat. Nos. 5,736,541 [Bunnell et al.], 6,251,895 B1 [Larsen et al.] and 7,022,698 B2 [Hamied et al.], the disclosure of each is totally incorporated herein by reference, and relate to the polymorphic forms of olanzapine and its use in pharmaceutical compositions. The API, olanzapine, has been isolated and characterized in several different free-base, polymorphic forms with each polymorph demonstrating a different stability profile and each subject to formulation changes suitable for use as a final dose product.
U.S. Pat. No. 5,120,850 [Bod et al.] and U.S. Pat. No. 5,128,477 [Bod et al.], the disclosure of each being totally incorporated herein by reference, relates to the selective crystallization or precipitation of two morphologically homogeneous forms of famotidine, a thiazole derivative. In U.S. Pat. No. 4,283,408 [Hirata et al.], the disclosure of which is totally incorporated herein by reference, famotidine and its pharmaceutically acceptable salts were formulated into gastric acid secretion inhibitors.
Recently, U.S. Pat. No. 6,987,111 82 [Greco et al.], the disclosure of which is totally incorporated herein by reference, discloses pharmaceutical compositions possessing long acting and/or extended release profiles incorporating the pamoate salts of aripiprazole, olanzapine and haloperidol. The inventors' observations contained in their claims purports to the physical appearance of the salt as a needle, or as crystalline, however no polymorphic examination, dissolution profile, bioavailability or pharmacokinetics was reported.
An important issue surrounding the current unprecedented activity in generic drug development is the evaluation of existing pharmaceutical products to identify their polymorphic behavior and to incorporate the correct polymorph into a generic commercial offering. Simultaneously, the generic product must exhibit a favorable impurity profile compared to the original, innovator product. Frequently for older drug products, the degree to which the active ingredient may be present in one or more polymorphic forms has not been explored or well characterized (if at all). Different polymorphic forms can radically influence a drug's solubility and result in a dramatically altered pharmacokinetic behavior for the patient.
To demonstrate the preceding assertion, U.S. Pat. No. 3,326,896 [Holstius] is illustrative, and the disclosure of which is totally incorporated herein by reference. The author discloses three embonic (pamoic acid) addition salts free from unpleasant taste and local anesthetic properties, and useful for the treatment of depression. The addition salt of 5-(3-dimethylaminopropyl)dihydro-5H-dibenz-[b,f]-azepine, (imipramine), was absorbed more slowly than the corresponding hydrochloride salt. Processes for making the embonic acid addition salts in aqueous and organic media were also disclosed. A review of the reported laboratory work reveals an anomalous observation in that the same “melting point” was reported for the pamoate salt of 5-(3-dimethylaminopropyl)-10,11-dihydro-5H-dibenz[bf]azepine as for 5-(3-methylaminopropyl)-10,11-dihydro-5H-dibenz[bf]azepine derivative. Both “melting points” were reported as 125-150° C. even though they are different compounds prepared under the same aqueous conditions. Melting ranges of this magnitude are generally associated with the presence of impurities and/or the presence of solvates/hydrates. In connection with the material the authors isolated, no crystalline forms were observed or claimed, and indeed, no attempt was made to characterize crystalline forms through techniques such as microscopy or X-ray powder diffraction patterns. Further, no calorimetry was performed thus clues gleaned from heats of fusion or heats of hydration were not provided. Interestingly, the author claims the embonic acid addition salt of 5-(3-dimethylaminopropyl)-10,11-dihydro-5H-dibenz[b,f]azepine, however the salt is not characterized as the 1:1 salt or as the 2:1 salt or some mixture thereof. Perhaps the broad melting point reported in the specification suggests the presence of impurities and/or the presence of unidentified solvates or hydrates.
With the existing commercial need and societal demand for generic drug products, the current invention is directed toward novel polymorphic forms of imipramine pamoate and their subsequent purification.